Purpose: This phase I study was conducted to evaluate the safety and pharmacokinetics of YM155, a potent, selective survivin inhibitor, in combination with erlotinib in patients with EGFR TKI refractory advanced non-small cell lung cancer (NSCLC). Methods: The pimary objectives were to evaluate the safety and tolerability of YM155 at escalating doses (3.6, 4.8, 6.0, and 8.0 mg/m2/days) administered every 3 weeks as continuous intravenous infusion over 168 h in combination with erlotinib at a fixed dose (150 mg, once a day). Secondary objectives were to assess the pharmacokinetics of YM155, antitumor activity, and the relationship between biomarkers and efficacy. The changes in survivin expression in biopsied tumor pre- and post-YM155 administration and serum cytokine levels were also analyzed. Results: Fifteen patients were treated. The most common YM155-related adverse event was the presence of urine microalbumin, whereas grades 3/4 toxicities were rare. One patient who received 4.8 mg/m2/days YM155 developed a dose-limiting grade 2 serum creatinine elevation. YM155 exposure in plasma showed dose proportionality across all dose ranges tested. No pharmacokinetic interaction occurred between YM155 and erlotinib. The serum cytokines IL-8, G-CSF, and MIP-1b showed decreasing trends in patients who achieved progression-free survival of ≥ 12 weeks. Durable stable disease for ≥ 24 weeks was observed in two patients. Conclusion: Up to 8.0 mg/m2/days YM155 administered every 3 weeks in combination with erlotinib exhibited a favorable safety profile and moderate clinical efficacy. These results suggest that inhibiting survivin is a potential therapeutic strategy for select patients with EGFR TKI refractory NSCLC. Trial registration: UMIN000031912 at UMIN Clinical Trials Registry (UMIN-CTR).
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